Anderson 2011 Am J Physiol Heart Circ Physiol
|Anderson EJ, Rodriguez E, Anderson CA, Thayne K, Chitwood WR, Kypson AP (2011) Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am J Physiol Heart Circ Physiol 300:H118-24.|
Abstract: Progressive energy deficiency and loss of cardiomyocyte numbers are two prominent factors that lead to heart failure in experimental models. Signals which mediate cardiomyocyte cell death have been suggested to come from both extrinsic (e.g. cytokines) and intrinsic (e.g. mitochondria) sources, but the evidence supporting these mechanisms remain unclear, and virtually non-existent in humans. In this study, we investigated the sensitivity of the mitochondrial permeability transition pore (mtPTP) to calcium (Ca2+) using permeabilized myofibers of right atrium obtained from diabetic (N = 9) and non-diabetic (N = 12) patients with coronary artery disease undergoing non-emergent coronary revascularization surgery. Under conditions that mimic the energetic state of the heart in vivo (pyruvate, glutamate, malate and 100 μM ADP), cardiac mitochondria from diabetic patients show an increased sensitivity to Ca2+-induced mtPTP opening as compared to non-diabetic patients. This increased mtPTP Ca2+-sensitivity in diabetic heart mitochondria is accompanied by a substantially greater rate of mitochondrial H2O2 emission (mtH2O2) under identical conditions, despite no differences in respiratory capacity under these conditions or mitochondrial enzyme content. Activity of the intrinsic apoptosis-pathway mediator, caspase-9, was greater in diabetic atrial tissue, while activity of the extrinsic-pathway mediator, caspase-8, was unchanged between groups. Furthermore, caspase-3 activity was not significantly increased in diabetic atrial tissue. These data collectively suggest that the myocardium in diabetic patients has a greater overall propensity for mitochondrial-dependent cell death, possibly as a result of metabolic stress-imposed changes that have occurred within the mitochondria, rendering them more susceptible to insults such as Ca2+ overload. In addition, they lend further support to the notion that mitochondria represent a viable target for future therapies directed at ameliorating heart failure and other co-morbidities that come with diabetes.
• Keywords: Ca2+, H2O2, mt-Permeability transition
• O2k-Network Lab: US NC Greenville Anderson EJ
Labels: Pathology: Diabetes Stress:Oxidative stress;RONS Organism: Human Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: OXPHOS, ET